This invention relates to a process for making phosphodiesterase IV (PDE IV) inhibitors which are useful in treating asthma and other diseases mediated by PDE IV. More particularly, this application describes a process for making and purifying a chiral bisaryl alcohol, an intermediate compound necessary for the preparation of PDE IV inhibitors such as CDP 840, by asymmetric bioreduction of a pro-chiral ketone.
Many hormones and neurotransmitters modulate tissue function by elevating intra-cellular levels of adenosine 3 ', 5'-cyclic monophosphate (cyclic AMP or cAMP). The role of cAMP as a second messenger is well recognized. It is responsible for transducing the effects of a variety of extracellular signals, including hormones and neurotransmitters. The level of intracellular cAMP is regulated through both its synthesis by adenyl cyclases and degradation by cyclic nucleotide phosphodiesterases (PDE). PDEs form a family of at least seven enzyme isotypes (I-VII) which differ in their affinity for cAMP and/or cGMP, subcellular localization and regulation (Beavo J. A. and Reifsnyder D. H. (1990) Trends Pharmacol. Sci. 11 150-155; Conti M. et al., (1991) Endocrine Rev. 12 218-234). The clinical effects of a number of drugs can be rationalized on the basis of their selectivity for a particular PDE isotype. For example, the cardiotonic drugs milrinone and zaprinast are PDE III and PDE V inhibitors respectively. (Harrison S. A. et al., (1986) Mol. Pharmacol. 29 506-514; Gillespie P. G. and Beavo J. (1989) Mol. Pharmacol. 36 773-781). The anti-depressant drug, rolipram functions as a selective PDE IV inhibitor. (Schneider H. H. et al., (1986) Eur. J. Pharmacol. 127 105-115.).
The availability of PDE isotype selective inhibitors has enabled the role of PDEs in a variety of cell types to be investigated. In particular it has been established that PDE IV controls the breakdown of cAMP in many inflammatory cells, for example, basophils (Peachell P. T. et al., (1992) J. Immunol. 148 2503-2510) and eosinophils (Dent G. et al., (1991) Br. J. Pharmacol. 103 1339-1346) and that inhibition of this isotype is associated with the inhibition of cell activation. Consequently PDE IV inhibitors are currently being developed as potential anti-inflammatory drugs particularly for the prophylaxis and treatment of asthma.
Several compounds that act as PDE IV inhibitors, including CDP 840, as well as methodology for their production, are disclosed in WO 94/14742, published Jul. 7, 1994, which is hereby incorporated by reference. These compounds are useful as anti-inflammatory drugs, particularly for prophylaxis and treatment of asthma as well as for treatment of other inflammatory diseases. However, WO 94/14742 does not describe an efficient chemical means for making a chiral bisaryl alcohol intermediate for use in production of PDE IV inhibitors. The benefit of such invention is a more efficient means of making PDE IV inhibitor compounds that require a bisaryl alcohol intermediate, such as CDP 840, and greater yield.
The present invention describes a biotransformation process for the production of a specific chiral alcohol intermediate important in the chemical synthesis of PDE IV inhibitors. There is currently no known chemical method for production of a chiral bisaryl alcohol of the invention, which is a key intermediate used to make CDP 840 and other PDE IV inhibitors. The chiral compound of the invention is a necessary intermediate in producing PDE IV inhibitors. Its exceptional optical purity, when made by the bioprocess of the invention, allows production of the PDE IV inhibitor in fewer steps and greater yield than if a synthetically produced racemic mixture were used.
Microorganisms capable of reducing a prochiral bisaryl ketone to a chiral bisaryl alcohol for synthesizing PDE IV inhibitors, such as CDP 840, are used in the invention. Moreover, the enantiomeric purity of the compound of the invention produced in microorganisms permits a greater yield of PDE IV inhibitor and requires less steps than chemical synthesis of the intermediates for making the inhibitors. Thus, the present invention provides an optically pure intermediate for use in making PDE IV inhibitors and permits synthesis of the inhibitor in fewer steps.